ABSTRACT Our prior work indicates that women with premenstrual dysphoric disorder (PMDD) may be more vulnerable to dysphoric mood states induced by changes in gonadal hormones and their neuroactive metabolites, and not resulting from absolute levels per se. One objective of the proposed research is to determine if a continuous oral contraceptive (OC) regimen that eliminates the pill free interval (PFI) and produces stable, low endogenous hormone levels will prevent the expression of PMDD symptoms. A second objective is to demonstrate that changing hormones trigger affective symptoms in PMDD, and to establish which gonadal hormones and their neuroactive metabolites are associated with symptoms. Eighty one women with prospectively confirmed PMDD will be randomized and complete one of three, 13 week treatment arms: Treatment #1) continuous administration of 20 ug ethinyl estradiol/3mg drospirenone [EE/P]; Treatment #2) interrupted EE/P, substituting placebo for EE/DRP during weeks 4, 8, & 12; Treatment #3) continuous placebo. The primary outcome measure will be the total PMDD symptom score assessed daily at baseline and throughout the treatments. Secondary measures will include Response Rate, mood and social adjustment scales. Serum levels of estradiol (E2) and P, as well as plasma levels of neuroactive steroids, allopregnanolone, allotetrahydroDOC, pregnanolone and pregnenolone sulfate, all potent modulators of the GABA receptor will be sampled on cycle days 17, 21, 25, 2, & 5 at pretreatment and also during treatment A month 3. Primary predictions are: 1) Continuous EE/P (arm #1) will be associated with a significant reduction in PMDD symptoms relative to pretreatment levels, and will be associated with lower symptom levels in months 2 and 3 of treatment relative to both placebo and interrupted EE/P (arms #2 and #3); 2) Women treated with interrupted OC (arm #2) will show symptom severity similar to women treated with placebo (arm #3), and will continue to show cyclicity of symptoms though there will be a shift in peak symptoms to the follicular phase, corresponding primarily to the changes in E2 induced during the PFI; 3) the increase in E2 during the PFI in women treated with interrupted OC (arm #2) will predict the development and severity of symptoms in that group; and 4) since OCs suppress the synthesis of neurosteroids, the magnitude of the change in neuroactive steroids from days 17 25 to days 2- 5 will predict PMDD symptoms in the placebo group, but not in the women treated with OCs (arms #1 and #2). The results of this study are expected to advance our knowledge on the pathophysiology of PMDD and help illuminate a substrate for affective dysregulation in women. Confirmation of the role of hormonal change in precipitating PMDD will suggest therapeutic targets for future research. Premenstrual Dysphoric Disorder (PMDD), characterized by the cyclic recurrence of affective symptoms and resultant impairment in function, has substantial morbidity and the identified treatments are of limited effectiveness. Evidence indicates that dysphoric mood states in PMDD are induced by normal changes in gonadal steroid hormones (estradiol and progesterone), rather than by exposure to elevated hormone levels. By extension, eliminating changes in gonadal hormones with continuous oral contraceptive administration, as the planned research intends, should prevent the appearance of dysphoric symptoms. The results of this research are expected to increase our knowledge regarding the causes of PMDD and to inform the design of subsequent research establishing the use of an acceptable form of therapy with minimal side effects in PMDD.